Some of the information set forth herein has been published. See Suciu-Foca, et al., New Differentiation Antigens Associated with the Growth and Maturation of B Lymphocytes, J. of Immunology, 1988, 104:395-403. The above-identified paper was distributed by the publisher on Jan. 16, 1988.
Throughout this application several publications are referenced by Arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
The transition of T and B lymphocytes from their resting state to a state of functional maturity involves distinct steps of activation, proliferation and differentiation, each requiring specific signals. After activation by mitogens, antigens, viruses, or by antibodies to structures associated with the antigen-receptor, lymphocytes express on their surface new differentiation antigens which are absent from the membrane of resting cells (39,40).
The physiologic role of most activation antigens is as yet unknown, although some antigens, such as those recognized by the anti-Tac antibody or by the anti-T9 antibody, were shown to serve as receptors for interleukin 2 (IL-2) and for transferrin, respectively (40). It is suspected that other activation antigens may also serve as receptors for hormones, lymphokines, monokines, or for cell-cell interaction signals which regulate the growth, differentiation, and network of communications within, and between, the T cell and B cell compartment. Some differentiation antigens are T or B cell lineage specific, whereas others are expressed both by activated T and B lymphocytes (39, 40).
The proliferation and subsequent differentiation of B lymphocytes is regulated by at least two distinct types of lymphokines: one which promotes their growth (B cell growth factor or BCGF) and the other their differentiation into immunoglobulin-secreting cells (B cell differentiation factor or BCDF) (1-4).
These lymphokines are produced primarily by T lymphocytes although B cells activated with Staphylococcus aureus Cowan 1 (SAC) (5,6) or transformed with Epstein-Barr Virus (EBV) are also capable of secreting autocrine growth factors (6,7). Recently some of those factors have been characterized biochemically, and the gene encoding the synthesis of at least one of them has been cloned (4). However, the molecular structure of the B cell receptor(s) for growth and differentiation factors is still unknown.
The identification and characterization of such receptors is of obvious importance for understanding the mechanisms which regulate the growth and differentiation of B-lymphocytes.
Several studies have reported monoclonal antibodies specific for resting (8,9) or for activated B lymphocytes (10) that inhibit (9,10) or, alternatively, promote (8) the activation and differentiation of B lymphocytes. Monoclonal antibodies reacting with molecules involved in leukocyte cell interaction were also shown to mimic the biological effects of B cell stimulatory factors suggesting that they react with molecules associated with BCGF-receptor structures (11). However, none of these monoclonal antibodies blocked the receptors of activated B cells for BCGF or BCDF.
The present application describe a new antigen, NDA4, which expressed on activated human T lymphocytes, on activated B cells, and on Epstein-Barr virus (EBV)-transformed B cells. Murine monoclonal antibodies (MoAb) that recognize this new differentiation antigen precipitate a distinct cell surface antigen of m.w. 46,000 and stimulate the proliferation and the maturation of EBV-transformed lymphoblastoid B cell lines (LBCL). This suggests that the structures recognized by MoAb NDA4 may play a role in regulation of B cell growth and differentiation.